Is EBLN2 p.Asp99His (c.295G>C) pathogenic?

EBLN2 p.Asp99His (c.295G>C) is classified Uncertain significance in EBLN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: ambiguous (0.4802); Ultra-rare (popmax 0.0166%, mid).

How common is EBLN2 p.Asp99His (c.295G>C) in the general population?

EBLN2 p.Asp99His (c.295G>C) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about EBLN2 p.Asp99His (c.295G>C)?

AlphaMissense predicts ambiguous (score 0.4802) — an in-silico prediction, not a clinical call.

EBLN2 p.Asp99His

c.295G>C · VCV3506393

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4802 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4802	ambiguous
REVEL	0.095	moderately benign-leaning
SaProt	LLR -7.55	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.24, phastCons 0.017
Regional constraint	o/e 1.22	unconstrained · MANE · 815 bp · p 5.3e-05 · regional, not allelic
Overall
CADD	14.21	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0166% Middle Eastern · 1/6,014 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00212% 34/1,606,510 alleles · ultra-rare exomes 30/1,454,294 · genomes 4/152,216 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,014
Remaining individualsnot grpmax-eligible	0.00483%	20,717
Admixed American	0.0035%	28,592
South Asian	0.00223%	44,913
European (non-Finnish)	0.00221%	45,305

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: EBLN2
Protein: p.Asp99His
Coding: c.295G>C
MANE Select: NM_018029
Type: single nucleotide variant
Location: chr3:73062376 (GRCh38)
Gene constraint: LOEUF 1.962 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.89

Full EBLN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EBLN2 p.Ala106Thr Uncertain significance ★ ⚠ same type
EBLN2 p.Ala107Val Uncertain significance ★ ⚠ same type
EBLN2 p.Ala165Gly Uncertain significance ★ ⚠ same type
EBLN2 p.Ala176Gly Uncertain significance ★ ⚠ same type
EBLN2 p.Ala214Val Uncertain significance ★ ⚠ same type
EBLN2 p.Arg160Gly Uncertain significance ★ ⚠ same type
EBLN2 p.Arg160Ser Uncertain significance ★ ⚠ same type
EBLN2 p.Arg184Cys Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ebln2-p-asp99his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown